RECUPERO DI SPERMATOZOI RECUPERO DI SPERMATOZOI

NELLA SINDROME DI KLINEFELTERNELLA SINDROME DI KLINEFELTER

Massimiliano TimpanoMassimiliano Timpano

UNIVERSITÀ DEGLI STUDI DI TORINOA.O. Città della Salute e della Scienza di Torino –

MolinetteDivisione Universitaria di Urologia - Direttore: Prof. B. Frea S.S.C.V.D. per l’Andrologia – Responsabile: Dott. L. Rolle

Fertility in Klinefelter Fertility in Klinefelter syndromesyndrome

Practically all ejaculates from patients with 47,XXY Practically all ejaculates from patients with 47,XXY karyotype show karyotype show azoospermia azoospermia

Sperm are observed only rarely, and exceptional cases Sperm are observed only rarely, and exceptional cases of spontaneous paternity have been reportedof spontaneous paternity have been reported

Lanfranco et al., Lanfranco et al., Lancet 2004; 364: 273-83Lancet 2004; 364: 273-83

Reported pregnancies after ICSI treatment with Reported pregnancies after ICSI treatment with ejaculated spermatozoa of patients with non-ejaculated spermatozoa of patients with non-

mosaic KS.mosaic KS.

Lanfranco et al., Lanfranco et al., Lancet 2004; 364: 273-83Lancet 2004; 364: 273-83

Human Reproduction 11: 1644-9, 1996Human Reproduction 11: 1644-9, 1996

Testicular sperm recovery in nine Testicular sperm recovery in nine 47,XXY Klinefelter patients.47,XXY Klinefelter patients.

Tournaye H, Staessen C, Liebaers I, Van Assche E, Tournaye H, Staessen C, Liebaers I, Van Assche E, Devroey P, Bonduelle M, Van Steirteghem A.Devroey P, Bonduelle M, Van Steirteghem A.

Centre for Reproductive Medicine, University Hospital, Dutch-speaking Brussels Free University Centre for Reproductive Medicine, University Hospital, Dutch-speaking Brussels Free University

(Vrje Universitet Brussel), Laarbeeklaan 101, B-1090 Brussels, Belgium(Vrje Universitet Brussel), Laarbeeklaan 101, B-1090 Brussels, Belgium

Reported pregnancies after ICSI treatment with Reported pregnancies after ICSI treatment with testicular spermatozoa of patients with KS.testicular spermatozoa of patients with KS.

Lanfranco et al., Lanfranco et al., Lancet 2004; 364: 273-83Lancet 2004; 364: 273-83

Aksglaede et al., Hum Reprod 2006; 12:39-48Aksglaede et al., Hum Reprod 2006; 12:39-48Wikstrom AM & Dunkel L, Horm Res 2008; 69:317-326Wikstrom AM & Dunkel L, Horm Res 2008; 69:317-326

Natural history of seminiferous tubule degeneration Natural history of seminiferous tubule degeneration in KSin KS

The degenerative process may start even during fetal life, The degenerative process may start even during fetal life, as studies of aborted fetuses at gestational ages 18–22 as studies of aborted fetuses at gestational ages 18–22 weeks have shown (Murken et al., Lancet 1974 ; Coerdt et weeks have shown (Murken et al., Lancet 1974 ; Coerdt et al., Pediatr Pathol 1985).al., Pediatr Pathol 1985).

In prepubertal KS boys, the focal nature of the In prepubertal KS boys, the focal nature of the degeneration process is already evident, since the few degeneration process is already evident, since the few seminiferous tubules containing spermatogonia are seminiferous tubules containing spermatogonia are surrounded by Sertoli-cell-only tubules.surrounded by Sertoli-cell-only tubules.

In KS, immature Sertoli cells are incapable during puberty In KS, immature Sertoli cells are incapable during puberty of transforming into the adult mature cell type.of transforming into the adult mature cell type.

Natural history of seminiferous tubule degeneration Natural history of seminiferous tubule degeneration in KSin KS

Major histological changes in the testes coincide with the Major histological changes in the testes coincide with the pubertal activation of the pituitary-gonadal axis.pubertal activation of the pituitary-gonadal axis.

With age, fibrosis and hyalinization of the interstitium and With age, fibrosis and hyalinization of the interstitium and peritubular connective tissue increases, and already in 12- peritubular connective tissue increases, and already in 12- to 14-year-old KS boys, huge hyperplastic Leydig cells can to 14-year-old KS boys, huge hyperplastic Leydig cells can be visible in testicular biopsiesbe visible in testicular biopsies

The degeneration of germ cells in KS may be because of a The degeneration of germ cells in KS may be because of a primary effect of the extra X chromosome on the primary effect of the extra X chromosome on the development and function of the germ cells or adverse development and function of the germ cells or adverse influence on the supporting somatic cells including the influence on the supporting somatic cells including the Leydig and Sertoli cells.Leydig and Sertoli cells.

Aksglaede et al., Hum Reprod 2006; 12:39-48Aksglaede et al., Hum Reprod 2006; 12:39-48Wikstrom AM & Dunkel L, Horm Res 2008; 69:317-326Wikstrom AM & Dunkel L, Horm Res 2008; 69:317-326

Wikstrom et al., JCEM 2004Wikstrom et al., JCEM 2004

• Volume testicolareVolume testicolare

NONO• FSHFSH NONO• Inibina BInibina B NONO• Rapporto inibina B/FSHRapporto inibina B/FSH

NONO

• Età Età SÌSÌ

Urology 2006; 68: 1082-1086Urology 2006; 68: 1082-1086

With the aid of an operating microscope for microdissection (micro-TESE), With the aid of an operating microscope for microdissection (micro-TESE), the sperm retrieval rate the sperm retrieval rate

was successful in 56.7% of 74 cases with non-was successful in 56.7% of 74 cases with non-mosaic KS.mosaic KS.

Tournaye et al., Int J Androl 1997; 20:69-73Tournaye et al., Int J Androl 1997; 20:69-73Friedler et al., Hum Reprod 2001; 16:2616-2620 Friedler et al., Hum Reprod 2001; 16:2616-2620

Staessen et al., Hum Reprod Update 2003; 9:319-330Staessen et al., Hum Reprod Update 2003; 9:319-330Kamischke et al., J Androl 2004; 25:586-592Kamischke et al., J Androl 2004; 25:586-592

Testicular tissue may be successfully cryopreserved Testicular tissue may be successfully cryopreserved

in patients with non-mosaic KS without in patients with non-mosaic KS without

significantly compromizing fertilization and implantation significantly compromizing fertilization and implantation

rates.rates.

As germ cell depletion is already evident in the testes As germ cell depletion is already evident in the testes

of 47,XXY infants and rapidly progresses, of 47,XXY infants and rapidly progresses,

cryopreservation of semen samples may preserve cryopreservation of semen samples may preserve

future fertility in those young KS men identified before future fertility in those young KS men identified before

the time at which they present with the time at which they present with

infertility. infertility.

25 pazienti con cariotipo 47, XXY – età media 25 pazienti con cariotipo 47, XXY – età media 35 anni35 anni

Recupero positivo in 8 pazienti (32%)Recupero positivo in 8 pazienti (32%)

• FSHFSH 23 UI/L23 UI/L• VolumeVolume 4 cc4 cc

• Età Età 31 anni31 anni

• FSHFSH 30.5 UI/L30.5 UI/L• VolumeVolume 3.5 cc3.5 cc

• Età Età 38 anni38 anni

Casistica personaleCasistica personale

In studies of chromosomal abnormalities In studies of chromosomal abnormalities in ejaculated spermatozoa from patients with in ejaculated spermatozoa from patients with

KS the incidence of sex chromosomal KS the incidence of sex chromosomal hyperploidy varied from 0.9% to 2.5% in hyperploidy varied from 0.9% to 2.5% in

the mosaic form and from 2.5% to 21.6% the mosaic form and from 2.5% to 21.6% in the non-mosaic form. in the non-mosaic form.

The proportion of hyperploid spermatozoa The proportion of hyperploid spermatozoa in men with KS does not correlate with the in men with KS does not correlate with the

proportion of 47,XXY cells in somatic tissues. proportion of 47,XXY cells in somatic tissues.

Overall, a higher risk of fathering a 47,XXY or Overall, a higher risk of fathering a 47,XXY or 47,XXX child after successful fertilization 47,XXX child after successful fertilization treatment has to be taken into account.treatment has to be taken into account.

An increased incidence of autosomal aneuploidies An increased incidence of autosomal aneuploidies in spermatozoa from subjects with non- in spermatozoa from subjects with non-

mosaic KS has been demonstrated. mosaic KS has been demonstrated. Hennebicq et al. Hennebicq et al. (2001) described a higher (2001) described a higher

frequency of disomy 21 in the spermatozoa of a non-frequency of disomy 21 in the spermatozoa of a non-mosaic Klinefelter patient, thus indicating an mosaic Klinefelter patient, thus indicating an

important risk of trisomy 21 in offspring of important risk of trisomy 21 in offspring of patients with KS when these patients were patients with KS when these patients were

candidates for ICSI. candidates for ICSI. Morel et al. Morel et al. (2003) found a significant difference in (2003) found a significant difference in

the frequency of autosomal disomy for the frequency of autosomal disomy for chromosomes 13, 18 and 21 in Klinefelter patients. chromosomes 13, 18 and 21 in Klinefelter patients.

Patients with Klinefelter syndrome, including the non-Patients with Klinefelter syndrome, including the non-mosaic type, may no longer be considered infertile mosaic type, may no longer be considered infertile a a prioripriori, as ICSI offers the opportunity for procreation even , as ICSI offers the opportunity for procreation even when spermatozoa in the ejaculate are lacking. when spermatozoa in the ejaculate are lacking.

Surgical sperm retrieval has revealed spermatozoa in up Surgical sperm retrieval has revealed spermatozoa in up to one half of non-mosaic Klinefelter patients selectively to one half of non-mosaic Klinefelter patients selectively referred to centers specialized in assisted reproduction referred to centers specialized in assisted reproduction techniques. techniques.

The incidence of sex chromosomal hyperploidy and The incidence of sex chromosomal hyperploidy and autosomal aneuploidies is higher in spermatozoa from autosomal aneuploidies is higher in spermatozoa from Klinefelter patients than from normal men. Klinefelter patients than from normal men.

Chromosomal errors may be transmitted to the offspring Chromosomal errors may be transmitted to the offspring of men with Klinefelter syndrome. of men with Klinefelter syndrome.

The genetic implications of the fertilization procedures The genetic implications of the fertilization procedures including pretransfer or prenatal genetic evaluation must including pretransfer or prenatal genetic evaluation must be explained to the patients and their partners.be explained to the patients and their partners.

FERTILITY IN KLINEFELTER SYNDROMEFERTILITY IN KLINEFELTER SYNDROME

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